Dopaminergic afferents arising from the ventral tegmental (VTA) area and projecting to the nucleus accumbens (ACb)are key elements of brain circuits that subserve arousal, motivation, and reinforcement. Increased dopamine neurotransmission within this mesoaccumbal pathway has been implicated in the mediation of the reinforcing effects of psychostimulants, alcohol, and other drugs of abuse. [unreadable] [unreadable] Previous studies have shown toluene inhalation produces reinforcing effects in animal models and is abused by humans. Although acute exposure of rats to toluene increases dopamine release in the dorsal striatum similar effects have not been reported in the ACb. These findings have led to the hypothesis that a dopamine-independent mechanism mediates the abuse liability of toluene and other inhalants. Anatomical studies, however, have shown that the ACb consists of two sub-regions termed the shell and the core. Heterogeneity of the VTA and in the responsiveness of VTA dopamine neurons to several drugs of abuse has been reported. [unreadable] [unreadable] We conducted a series of studies to determine whether there are sub-region-specific effects of toluene on neuronal activity in the VTA and ACb. Using in-vitro electrophysiology, we have now shown that behaviorally relevant concentrations of toluene directly stimulates dopamine neurons in the VTA but not in surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-dopamine containing neurons, the magnitude of VTA dopamine neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in-vivo microdialysis to monitor dopamine release, we show that perfusion of toluene directly into the VTA increases dopamine concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACb. The magnitude of the dopamine response to toluene also varied as a function of the VTA sub-region evaluated. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA dopamine neurons, thereby enhancing dopamine transmission in the ACb. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA dopamine neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse. Importantly, they suggest that the mesoaccumbal pathway may also contribute to the abuse of toluene and other inhalants. [unreadable] [unreadable] We previously demonstrated the existence of a tonically active kappa-opioid receptor (KOPr) system located in the ACb that inhibits the basal activity of dopamine neurons in the ACb. This same opioid system is up-regulated in response to the repeated use of alcohol and psychostimulants suggesting that this neuroadaptation may underlie alterations in behavior and mesolimbic dopamine transmission that occur following repeated drug use. We have tested this hypothesis using in-vivo microdialysis in conjunction with pharmacological and gene targeting techniques Our studies have revealed that acute alcohol exposure increases dopamine concentrations in the Acb and that this effect is enhanced in animals lacking KOPr. These findings demonstrate that inhibition of KOPR is associated with increased sensitivity of an individual to the dopamine-releasing effects of ethanol. They are particularly interesting in that they may provide a neurochemical basis for the recent demonstration that variations in the genes encoding both KOPr and its endogenous ligand, dynorphin, are associated with the risk for alcohol dependence in human subjects. [unreadable] [unreadable] We have gone on to examine the influence of KOPr blockade on alcohol self-administration and extracellular dopamine concentrations in the Acb. Microdialysis revealed a transient elevation of dopamine concentration within 5 min of ethanol access in controls that was abolished by KOPr blockade. Despite these neurochemical changes, KOPr blockade did not alter operant responding or ethanol intake, suggesting that the KOPr is not involved in ethanol-reinforced behavior under the limited conditions we studied. However, fundamental questions exist as to whether behavioral interactions of KOPr ligands with alcohol are observed following longer access to alcohol and/or with administration paradigms that result in the development of alcohol dependence. [unreadable] [unreadable] Preliminary studies conducted with our collaborators at the Karolinska Instituute (NIH and Karolinska Institute Collaborative Program In Postgraduate Education) have shown that expression of dynorphin, the endogenous ligand for the KOPr, is altered in the hippocampus of human alcoholics. KOPr is located on glutamatergic neurons in the hippocampus and has been implicated in the modulation of long-term depression (LTD). On-going studies are seeking to determine whether KOPr regulate glutamate transmission in the hippocampus and whether dysregulation of this opioid system contributes to the neurotoxic effects of alcohol on hippocampal function. Our preliminary data suggest that KOPr antagonist can not only prevent cognitive deficits produced by repeated high dose alcohol exposure but also prevent alterations in glutamatergic neurotransmission that occurs in the hippocampus following alcohol exposure. On-going studies are determining the mechanisms by which KOPr antagonism produces neuroprotection.